tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

In a phase I/II trial, vitamin D was shown to prevent chronic graft versus host disease (cGvHD) in patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). Carrillo-Cruz and colleagues followed up their trial with an assessment of the impact of SNPs in the vitamin D receptor (VDR) on the efficacy of vitamin D. Patients with the VDR FokI CT genotype showed the greatest protection from cGvHD after vitamin D treatment and allo-HSCT. These results facilitate the stratification of patients for whom vitamin D would be most beneficial.Hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer patients do not typically benefit from checkpoint inhibitors. Waks and colleagues analyzed the tumor-immune microenvironment before and after neoadjuvant chemotherapy in 96 patients with HR+/HER2 breast cancer. The immune microenvironment was found to change after treatment: a significant increase in genes associated with protumor M2-like macrophages was observed, compared with a decrease in CD8+ T cells and stromal tumor-infiltrating lymphocytes. These results suggest that the combination of chemotherapy with macrophage-targeting agents may be an effective immunotherapy approach in HR+/HER2 breast cancer.Surgical resection is an integral component of treatment for solid tumors; however, cancer cells often are not completely removed at the tumor margins, leading to recurrence. van Keulen and colleagues describe a novel imaging strategy for use during surgical tumor excision. Twelve head and neck cancer patients received systemic administration of a tumor-specific contrast agent (panitumumab-IRDye800), and the tumors were visualized after surgery using a fluorescence imager. This fluorescence-based strategy consistently identified tumor margins and could have broad implications for surgical oncology.Comprehensive detection of targetable kinase fusions in lung cancer patients is clinically critical but technically challenging. Benayed and colleagues evaluated targeted RNAseq for the identification of gene fusions in patients where no clear mitogenic driver alteration was found by DNAseq-based panel testing. Actionable kinase fusions or MET exon 14 skipping was identified in 13% of cases that were previously determined to be fusion-negaive by DNAseq. Among the driver-negative samples tested by RNASeq, those with low tumor mutation burden were significantly enriched for gene fusions. Therefore, targeted RNASeq complementing large panel DNAseq can be effective in comprehensively uncovering targetable gene fusions.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

The FGFR pathway is thought to drive oncogenic progression of many tumor types. Bahleda and colleagues report on the results of a first-in-human phase I trial of erdafitinib (JNJ-42756493), a potent, oral pan-FGFR tyrosine kinase inhibitor, conducted on patients with advanced-stage disease with known genetic activation of the FGFR pathway. This agent was well-tolerated and showed promising efficacy, especially in urothelial carcinoma and cholangiocarcinoma patients with FGFR alterations. These results have the potential to influence future treatment of patients with FGFR positive tumors.Myelofibrosis is morphologically characterized by the presence of atypical megakaryocytes and bone marrow fibrosis. To determine whether elimination of these abnormal megakaryocytes has therapeutic benefit for myelofibrosis patients, Gangat and colleagues conducted a phase 1 study of alisertib, an aurora kinase A inhibitor and megakaryocyte differentiation agent. Alisertib was well-tolerated and provided a modest clinical benefit for spleen size and symptom burden. Moreover, alisertib normalized megakaryocyte morphology and reduced fibrosis in a substantial number of patients. This study underscores the role of megakaryocytes in myelofibrosis and highlights the feasibility of targeting this lineage in this disease.Cancer vaccines have long been considered a promising tool for cancer therapy. However, many potential vaccines have been ineffective in clinical trials, in part due to the immunosuppressive cancer microenvironment. In a phase I trial, Gatti-Mays and colleagues examined BN-CV301, a modified cancer vaccine expressing MUC1 and CEA tumor antigens, as well as costimulatory molecules. Treatment-related adverse events were relatively minor. Patients with mutant KRAS responded particularly well to this regimen – five out of six patients showed either a partial response or stable disease after BN-CV301 vaccination. This improved vaccine shows promise for further clinical evaluation.Pancreatic ductal adenocarcinoma is a highly lethal cancer due, in part, to a high rate of recurrence. Groot and colleagues developed and validated an assay to detect KRAS hotspot mutations in circulating tumor DNA (ctDNA) in a CLIA laboratory setting. Detection of mutant KRAS in ctDNA at the time of surgery was associated with a greater risk of recurrence, while rising mutant KRAS levels in ctDNA provided an early prediction of recurrence. In several instances, the detection of mutant KRAS in ctDNA outperformed the measurement of CA 19-9 in serum. This liquid biopsy test for mutant KRAS shows great promise for monitoring disease in pancreatic cancer patients, potentially leading to earlier intervention.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Resistance to antiangiogenic therapy has been shown to be partly mediated by MET. In a phase 1b/II clinical trial, Harding and colleagues examined the combination of antibodies against VEGFR-2 (ramucirumab) and MET (emibetuzumab) in advanced solid tumors. No dose-limiting toxicities were observed with this combination. This treatment regimen was particularly effective in hepatocellular carcinoma (HCC) with high MET expression, with a three-fold increase in progression-free survival observed in this population. These data suggest that combined inhibition of MET and VEGFR-2 is a promising treatment strategy for MET-positive HCC.Breast cancers with HER2 overexpression are highly aggressive, and patients often develop resistance to anti-HER2 therapy. In this phase I study for HER2-positive metastatic breast cancers (MBC), Li and colleagues assessed the combination of pyrotinib, a pan-ErbB inhibitor, with capecitabine. The combination of oral pyrotinib and capecitabine was well-tolerated and led to an overall response rate of 78.6% and a median progression-free survival of 22.1 months. Further clinical study of this combination is warranted in HER2-positive MBC.Follicular lymphoma is the most frequent indolent non-Hodgkin lymphoma. Although current treatments are effective for follicular lymphoma in the short term, most patients eventually relapse. Cox and colleagues report the results of a phase I clinical trial testing the intranodal administration of monocyte-derived IFNα-conditioned dendritic cells (IFN-DC) in refractory and relapsed patients. Combined with intranodal injections of rituximab, IFN-DC were well-tolerated and had an overall response rate of 50%. Furthermore, treatment with IFN-DC led to the infiltration of tumor-specific T cells. These results support the further use of IFN-DC.Biopsy samples must have sufficient tumor cellularity for all necessary diagnostic testing. Inadvertent sampling of fibrosis in lung cancer patients can yield inadequate biopsies, necessitating repeat procedures. Hariri and colleagues demonstrate the use of polarization sensitive OCT (PS-OCT) to accurately identify and distinguish fibrosis from tumor using birefringence detection, establishing a strong correlation between PS-OCT and histology for fibrosis quantification. PS-OCT reliably distinguished tumor regions with low fibrosis (≤20%) from those with &gt;20% fibrosis. The use of PS-OCT for this purpose will allow more accurate biopsy sampling to ultimately improve biopsy-mediated diagnostics.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

ErbB3 activation leads to resistance to EGFR inhibition in cancer, and the ErbB3 ligand neuregulin-1 (NRG1) is expressed in most head and neck squamous cell carcinomas (HNSCC). Duvvuri and colleagues conducted a window-of-opportunity trial in HNSCC patients to characterize the biologic activity of CDX-3379, a human anti-ErbB3 monoclonal antibody. CDX-3379 modulated pErbB3 in tumors and led to a marked clinical response in a subset of patients. These data provide the rationale for further development of CDX-3379 in HNSCC and additional ErbB3-/NRG-expressing tumor types.Malignant pleural mesothelioma (MPM) is a rare but lethal cancer. In a Phase Ib trial, Hassan and colleagues assessed the combination of pemetrexed and cisplatin with CRS-207, a live-attenuated Listeria monocytogenes vaccine expressing the mesothelin antigen in mesothelioma. This combination altered the tumor microenvironment to increase anti-tumor immune cells. Moreover, objective tumor responses were observed in most patients, with 89% demonstrating either complete response, partial response, or stable disease. These results support further clinical examination of the combination of chemotherapy and immune therapy in mesothelioma.Naturally occurring canine lung cancer shares many features with human disease, particularly in never-smokers. The molecular mechanisms of canine lung carcinogenesis, however, have not been assessed. Lorch and colleagues assessed the genomic landscape of canine lung cancer and found recurrent HER2 mutations in canine pulmonary adenocarcinoma, but not in adenosquamous or squamous cell carcinomas. The majority of the HER2 mutations observed were the V659E hotspot mutation that commonly occurs in human disease. These results further confirm naturally occurring canine lung adenocarcinoma as a comparable model to human lung cancers in never-smokers.4-1BB is a key costimulatory immunoreceptor which enhances cytolytic activity of T and NK cells when activated. Attempts to agonize the pathway via conventional antibodies, however, have been hampered by peripheral toxicity. To facilitate tumor-localized T-cell costimulation, Hinner and colleagues synthesized PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 led to effective 4-1BB-mediated costimulation of T cells in vitro in the presence of HER2-positive cancer cells. In a humanized mouse model, PRS-343 treatment led to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. These data support the clinical trials now underway assessing the efficacy and safety of PRS-343.
Comparison of the effectiveness and safety of treatment of incomplete second trimester abortion with misoprostol provided by midwives and physicians: a randomised, controlled, equivalence trial in Uganda
Authors: Susan Atuhairwe, Josaphat Byamugisha, Othman Kakaire, Claudia Hanson, Amanda Cleeve, Marie Klingberg-Allvin, Nazarius Mbona Tumwesigye, Kristina Gemzell-Danielsson
Journal: The Lancet Global Health (2022)
Chemical priming of natural killer cells with branched polyethylenimine for cancer immunotherapy
Authors: Seung Hee Choi, Hye Jin Kim, Joo Dong Park, Eun-Su Ko, Minwook Lee, Dae-Keum Lee, Jin-Ho Choi, Hye Jung Jang, Isaac Kim, Hae-Yun Jung, Keun-Hong Park, Kyung-Soon Park
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Due to their powerful immune surveillance activity and ability to kill and clear cancer cells, natural killer (NK) cells are an emerging anticancer immunotherapeutic agent. Therefore, there is much interest in developing efficient technologies that further enhance the therapeutic antitumor efficacy of NK cells. Methods To produce chemically primed NK cells, we screened polymers with various electric charges and examined their ability to enhance the cytotoxicity of NK cells. The effect of primary amine and electric charges of 25 kDa branched polyethylenimine (25KbPEI) was investigated by fluorination of the chemical. The role of 25KbPEI in determining the major priming mechanism was investigated in terms of calcium influx into NK cells. In vivo therapeutic efficacy of chemically primed NK cells was evaluated against solid tumor mouse model of triple negative breast and ovarian cancers. Results Chem_NK that was produced by the priming activity of 25KbPEI showed potent antitumor activity to various cancer cells. Chem_NK showed an activated phenotype, which manifests as increased expression of activating/adhesion/chemokine receptors and perforin accumulation, leading to enhanced migration ability and antitumor activity. Chem_NK display potent therapeutic efficacy against in vivo mouse model of triple negative breast and ovarian cancers. Fluorination of the primary amine group reduces the activity of 25KbPEI to prime NK cells, indicating that the cationic charge on the chemical plays a critical role in NK cell activation. A major priming mechanism was 25KbPEI-mediated calcium influx into NK cells, which occurred mainly via the Ca2 + -permeable non-selective cation channel transient receptor potential melastatin 2. Conclusions NK cells can be chemically primed with 25KbPEI to express potent antitumor activity as well as enhanced migration ability. Because PEI is a biocompatible and Food and Drug Administration-approved chemical for biomedical use, these results suggest a cost-effective and simple method of producing therapeutic NK cells.
Source of human milk (mother or donor) is more important than fortifier type (human or bovine) in shaping the preterm infant microbiome
Authors: Shreyas V. Kumbhare, William-Diehl Jones, Sharla Fast, Christine Bonner, Geert ‘t Jong, Gary Van Domselaar, Morag Graham, Michael Narvey, Meghan B. Azad
Journal: Cell Reports Medicine (2022)

Milk fortifiers help meet the nutritional needs of preterm infants receiving their mother's own milk (MOM) or donor human milk. We conducted a randomized clinical trial (NCT03214822) in 30 very low birth weight premature neonates comparing bovine-derived human milk fortifier (BHMF) versus human-derived fortifier (H2MF). We found that fortifier type does not affect the overall microbiome, although H2MF infants were less often colonized by an unclassified member of Clostridiales Family XI. Secondary analyses show that MOM intake is strongly associated with weight gain and microbiota composition, including Bifidobacterium, Veillonella, and Propionibacterium enrichment. Finally, we show that while oxidative stress (urinary F2-isoprostanes) is not affected by fortifier type or MOM intake, fecal calprotectin is higher in H2MF infants and lower in those consuming more MOM. Overall, the source of human milk (mother versus donor) appears more important than the type of milk fortifier (human versus bovine) in shaping preterm infant gut microbiota.
Corrigendum to “Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic” [Adv. Drug Delivery Rev. 179 (2021) 114000]
Authors: Samagra Jain, Abhijeet Venkataraman, Marissa E. Wechsler, Nicholas A. Peppas
Journal: Advanced Drug Delivery Reviews (2022)
Suprachoroidal Space Triamcinolone Acetonide: A Review in Uveitic Macular Edema
Authors: Simon Fung, Yahiya Y. Syed
Journal: Drugs (2022)

Triamcinolone acetonide injectable suspension for suprachoroidal use (Xipere®; SCS triamcinolone acetonide) is a corticosteroid approved in the USA for the treatment of macular edema associated with uveitis. Suprachoroidal injection of SCS triamcinolone acetonide results in preferential distribution into the posterior segment, which may reduce the risk of corticosteroid-related adverse events, such as cataracts and intraocular pressure (IOP) elevation. In a multicenter phase III trial in patients with non-infectious uveitic macular edema, SCS triamcinolone acetonide significantly and rapidly improved visual acuity and reduced signs of macular edema compared with sham treatment. SCS triamcinolone acetonide was generally well tolerated, with the most common adverse event being eye pain on the day of the procedure. The risk of corticosteroid-related IOP elevation appeared to be reduced in unrescued patients in the SCS triamcinolone acetonide group compared with patients in the sham control group who received rescue therapy. SCS triamcinolone acetonide is a novel and useful treatment option for uveitic macular edema. Uveitic macular edema is a major cause of blindness in the developed world. Intravitreal and periocular application of corticosteroids (e.g., triamcinolone acetonide) may be effective for uveitis and macular edema, but these routes are often associated with cataracts and corticosteroid-related intraocular pressure (IOP) elevation. Recently, a triamcinolone acetonide suspension for injection into the suprachoroidal space (Xipere®; SCS triamcinolone acetonide) has been approved for the treatment of uveitic macular edema. The suprachoroidal route preferentially distributes the drug to the back of the eye, resulting in a reduced risk of corticosteroid-related adverse events. In a pivotal clinical trial, SCS triamcinolone acetonide rapidly improved visual acuity and resolved macular edema in patients with non-infectious uveitis. SCS triamcinolone acetonide was generally well tolerated, with the most common ocular adverse event being eye pain on the day of procedure. In unrescued patients in the SCS triamcinolone acetonide group, there appeared to be a reduced risk of corticosteroid-related IOP elevation versus patients who received rescue therapy in the sham control group. SCS triamcinolone acetonide is a novel and useful treatment option for uveitic macular edema.
Use of a Digital Assistant to Report COVID-19 Rapid Antigen Self-test Results to Health Departments in 6 US Communities
Authors: Carly Herbert, Qiming Shi, Vik Kheterpal, Chris Nowak, Thejas Suvarna, Basyl Durnan, Summer Schrader, Stephanie Behar, Syed Naeem, Seanan Tarrant, Ben Kalibala, Aditi Singh, Ben Gerber, Bruce Barton, Honghuang Lin, Michael Cohen-Wolkowiez, Giselle Corbie-Smith, Warren Kibbe, Juan Marquez, Jonggyu Baek, Nathaniel Hafer, Laura Gibson, Laurel O’Connor, John Broach, William Heetderks, David McManus, Apurv Soni
Journal: JAMA Network Open (2022)

Importance Widespread distribution of rapid antigen tests is integral to the US strategy to address COVID-19; however, it is estimated that few rapid antigen test results are reported to local departments of health. Objective To characterize how often individuals in 6 communities throughout the United States used a digital assistant to log rapid antigen test results and report them to their local departments of health. Design, Setting, and Participants This prospective cohort study is based on anonymously collected data from the beneficiaries of the Say Yes! Covid Test program, which distributed more than 3 000 000 rapid antigen tests at no cost to residents of 6 communities (Louisville, Kentucky; Indianapolis, Indiana; Fulton County, Georgia; O’ahu, Hawaii; Ann Arbor and Ypsilanti, Michigan; and Chattanooga, Tennessee) between April and October 2021. A descriptive evaluation of beneficiary use of a digital assistant for logging and reporting their rapid antigen test results was performed. Interventions Widespread community distribution of rapid antigen tests. Main Outcomes and Measures Number and proportion of tests logged and reported to the local department of health through the digital assistant. Results A total of 313 000 test kits were distributed, including 178 785 test kits that were ordered using the digital assistant. Among all distributed kits, 14 398 households (4.6%) used the digital assistant, but beneficiaries reported three-quarters of their rapid antigen test results to their state public health departments (30 965 tests reported of 41 465 total test results [75.0%]). The reporting behavior varied by community and was significantly higher among communities that were incentivized for reporting test results vs those that were not incentivized or partially incentivized (90.5% [95% CI, 89.9%-91.2%] vs 70.5%; [95% CI, 70.0%-71.0%]). In all communities, positive tests were less frequently reported than negative tests (60.4% [95% CI, 58.1%-62.8%] vs 75.5% [95% CI, 75.1%-76.0%]). Conclusions and Relevance These results suggest that application-based reporting with incentives may be associated with increased reporting of rapid tests for COVID-19. However, increasing the adoption of the digital assistant may be a critical first step.
Strategies Adopted by Gay, Bisexual, and Other Men Who Have Sex with Men to Prevent <i>Monkeypox virus</i> Transmission — United States, August 2022
Authors: Kevin P. Delaney, Travis Sanchez, Marissa Hannah, O. Winslow Edwards, Thomas Carpino, Christine Agnew-Brune, Kaytlin Renfro, Rachel Kachur, Neal Carnes, Elizabeth A. DiNenno, Amy Lansky, Kathleen Ethier, Patrick Sullivan, Stefan Baral, Alexandra M. Oster
Journal: MMWR Morbidity and Mortality Weekly Report (2022)
Perceptions of Facilitators and Barriers to Implementation of Falls Prevention Programs in Primary Health Care Settings in China
Authors: Pengpeng Ye, Ye Jin, Yuliang Er, Xuejun Yin, Yao Yao, Bingqin Li, Jing Zhang, Rebecca Ivers, Lisa Keay, Leilei Duan, Maoyi Tian
Journal: JAMA Network Open (2022)

Importance Falls have become a major public health issue in China with population aging. Although falls prevention for older community-dwelling people has been included in the National Essential Public Health Service Package since 2009, there is limited understanding of the implementation of this program. Objective To identify the associated factors and provide recommendations to inform the better implementation of falls prevention in the Chinese primary health care system. Design, Setting, and Participants This qualitative study was conducted in 3 purposively selected cities in China from March 1 to June 7, 2021. Health administrators from the local health commission or bureau, staff members from local Centers for Disease Control and Prevention and primary health care facilities and community-dwelling older people were recruited, using a combination of purposive sampling and snowball sampling. Main Outcomes and Measures In-depth interviews were conducted with health administrators and focus groups with other participants. Data analysis followed the guidance of the Consolidated Framework for Implementation Research. Study outcomes included facilitators and barriers of implementing falls prevention for older people in the Chinese primary health care settings. A framework with recommendations was developed to inform the future intervention implementation. Results Among a total of 130 participants interviewed, 77 (59.2%) were female and the mean (SD) age was 47.4 (16.7) years. Clear recognition of the challenges and benefits of falls prevention, adaptive regionally tailored guidance plans, and continuous governmental policy and financial support were the major facilitators, whereas the major barriers consisted of insufficient confidence in delivering interventions and poor understanding of the falls burden, low recognition of the importance of falls prevention, limited multisectoral collaboration, and weak financial incentives. A 7-strategy embedded framework—including data-driven surveillance, audit and feedback, implementation strategy, workforce strengthening, community empowerment, internal services integration, and external enabling environment—was developed to foster successful implementation. Conclusions and Relevance This qualitative study identified major facilitators and barriers to the implementation of falls prevention for older people at the primary care level, which have the potential to contribute to better implementation of falls prevention for older people in the Chinese primary health care system.